Keywords:

Abstract

The
present review has been designed to update the recent developments on
the function of seminal vesicles and their role on male fertility. It
is indicated that the true corrected fructose level is a simple method
for the assessment of the seminal vesicular function. Measurement of seminal
fructose used universally as a marker of the seminal vesicle function
is not an appropriate approach due to its inverse relationship with the
sperm count. The true corrected fructose defined as log.
motile sperm concentrationmultiplied
by seminal fructose
concentrationhas
been shown to be a better marker of the seminal vesicle function.

Seminal
vesicular secretion is important for semen coagulation, sperm motility,
and stability of sperm chromatin and suppression of the immune activity
in the female reproductive tract.

In
conclusion, the function of seminal vesicle is important for fertility.
Parameters as sperm motility, sperm chromatin stability, and immuno-protection
may be changed in case of its hypofunction.

1
Introduction

The
seminal vesicles are composed of tubular alveoli and the mucosa is thrown
into an intricate system of folds with the epithelium overlaying the lamina
propria[1] . The seminal vesicles join the ampulla of the deferens
to form the beginning of ejaculatory ducts. Secretion of the seminal vesicles
constitutes the main (50%) and the last fraction of the ejaculates.

The
sex differentiation and the growth of seminal vesicles are highly dependent
on androgen[2,3]. Endogenous increase of serum testosterone
increased the secretory activity of the seminal vesicles in men[4].
In rats, any increase in serum testosterone or treatment with androgens
were associated with increased secretory activity of the seminal vesicles[2,5,6]
and increased seminal vesicle weight[7]. The seminal vesicles
possess 5 alpha-reductase activity, which converts testosterone to dihydrotestosterone,
the active hormone. More recently, it has been demonstrated that seminal
vesicles contain LH/hCG receptors, thus making this accessory reproductive
organ a potential target of direct regulation by LH[8].

The
secretory activity of the seminal vesicle is also regulated by the nervous
system and both the cholinergic and adrenergic neurons affect its function[9].
Muscarinic stimulus (cholinergic) increases nitric oxide production. Seminal
vesicle is a source of nitric oxide synthase in men[10]. An
increase in nitric oxide may improve the secretion of fructose by the
gland[11] .

The
seminal vesicles and prostate share the same blood supply with a comparable
chance of exposure to carcinogens. Despite these similarities, fewer than
60 adenocarcinomas of the seminal vesicles have been described so far,
whereas prostate cancer is the most common cancer in men[12].
The reason underlying this difference in cancer incidence is not clear.

Seminal
vesicles secrete a great variety of products[1] . The importance
of these secretions in male fertility needs to be elucidated. This review
attempts to demonstrate the role of seminal vesicles on male fertility.

2
Assessment of the
seminal vesicle function

Measurement
of seminal fructose has been used in almost all laboratories of the world
as a marker of the seminal vesicular function. The WHO includes the measurement
of this sugar to assess the function of these glands[13]. Several
studies have demonstrated an inverse relationship between sperm count
and seminal fructose concentration. To our knowledge, sperm count should
not be related to seminal vesicular function. This association seems to
be associated with any event occurring after ejaculation.

After
ejaculation, fructose is consumed by the spermatozoa in a process named
fructolysis. At higher sperm counts, the process will be stronger resulting
in a low seminal fructose concentration. That is the reason that seminal
fructose is higher in azoospermic and oligozoospermic than in normozoospermic
or polyzoospermic men. It can thus be concluded that it is impossible
to assess the function of the seminal vesicle simply from seminal fructose
determination[14-16]. In addition, there is no correlation
between fructose and sperm motility[15,16] despite that a lot
of evidences suggest that seminal vesicles are important for sperm motility[1].Seminal fructose concentration is inversely correlated with the
motile sperm concentration, suggesting that only the motile sperm consume
fructose after ejaculation[17].

This
can be seen that the value of seminal fructose concentration is not appropriate
as a marker of the secretory activity of the seminal vesicles, unless
the influence of sperm count on the fructose concentration can be excluded.
This is done by multiplying the seminal fructose by the logarithm of the
sperm concentration (corrected fructose) or the motile sperm count (true
corrected fructose)[16,18,19]. Lower levels of corrected seminal
fructose were observed in men with either low serum testosterone levels[1,16]
or with an obstructive process at the seminal vesicles[19].

Seminal
levels of the specific protein of the seminal vesicles (MHS-5)[20]
and the protein C inhibitor (PCI), a plasma serine protease inhibitor
of activated protein C[21], have also been used to assess the
seminal vesicle function. Other methods to assess seminal vesicles function
include transrectal ultrasonography (TRUS)[22,23] and magnetic
resonance imaging[24].

3
True corrected seminal fructose

The
corrected seminal fructose calculated as log.
sperm concentrationmultiplied
by seminal fructose
concentrationhas
been shown to be a better marker of seminal vesicle function than simple
measurement of the seminal fructose concentration[1,16,19,25-28].
Low levels of corrected seminal fructose have been observed in men with
hypofunction of the seminal vesicles[26,28] and this has been
related to male infertility. Subjects with hypofunction of the seminal
vesicles have low sperm motility, which itself may cause infertility[16,19].

Corrected
fructose is correlated with the sperm motility in men with normal sperm
motility whereas seminal fructose is not[16]. However, in asthenozoospermic
samples, we were unable to observe a relationship between the sperm motility
and the corrected fructose value[28]. Thus the corrected fructose
value is not a goodmarker
of the seminal vesicle function in infertile men.

We
have described a new approach to assess the seminal vesicle function based
on fructose measurement and motile sperm concentration. The value obtained
has been named true corrected fructose[18]. With this correction,
we have shown a prevalence of 47.6% with hypofunction of the seminal vesicle
in men attending our infertility service. Moreover, from 18 cases of asthenozoospermia,
12 was associated with seminal vesicle dysfunction. The finding is important
from the point of view of the diagnosis and treatment of male infertility.
The demonstration that several cases of asthenozoospermia were due to
a low seminal vesicle function will direct to appropriate treatment aiming
at the improvement of the function of these glands.

4
Test for androgen
activity

Seminal
vesicles are androgen-dependent and this property may be used as biological
marker of androgenic activity. Gonzales[4] has developed a
method to assess the androgen activity at the reproductive tract level
based on both the serum testosterone level and the corrected seminal fructose
level under the basal and the post-clomiphene stimulation. Men received
100 mg clomiphene citrate daily for 5 days. The second blood and semen
samples were obtained one day after the last administration of clomiphene.
Levels of serum testosterone were more related to thecorrected seminal fructose than to seminal fructose concentration[4].
Seventy-one percent of subjects with low serum testosterone levels had
low levels of corrected seminal fructose, whereas only 28% of the same
subjects had low levels of seminal fructose (uncorrected fructose). The
results suggest that corrected seminal fructose may be used as a biological
marker of androgen activity in the reproductive tract[4].

More
recent study has demonstrated that the true corrected seminal fructose
was a better marker of seminal vesicle function[18]. The combined
measurement of the serum testosterone level and the level of corrected
seminal fructose allows the diagnosis of hypoandrogenism and/or obstructive
process at the reproductive tract[25]. An increase in the serum
testosterone after clomiphene stimulation without increase in the corrected
or true corrected seminal fructose suggests an obstructive process at
the reproductive tract level, whereas absence of increase in serum testosterone
and corrected/true corrected seminal fructose levels may indicate hypogonadism[18].

Normal
levels of serum testosterone and low values of seminal fructose have been
found in men with azoospermia due to obstruction of the ejaculatory ducts[4,25,29].
One third of azoospermia and severe oligozoospermia have an obstruction
of the ejaculatory duct[30].

About
10% of azoospermic patients have congenital absence of the seminal vesicles
and vas deferens. Low seminal volume (<0.5 mL), low pH and low concentration
of seminal fructose with normal serum FSH levels are diagnostic criteria
for this condition[31]. Diagnosis is also possible through
measuring the seminal level of the specific protein of the seminal vesicle
(MHS-5). This protein is absent in agenesis of the seminal vesicle[20].
PCI is present at high concentrations in the seminal plasma of normal
subjects and is decreased in some infertile patients[21]. PCI was significantly
lower in the seminal plasma of patients with seminal vesicle and/or vasal
agenesis. This is another useful marker for agenesis of seminal vesicles
and/or the vas deferens[21].

Despite
that increased serum testosterone level is related to seminal vesicle function,
treatment with high doses of testosterone propionate results in diminished
levels of secretions of seminal vesicles and prostate, probably due to down
regulation[32].

5
Physiology and physiopathology of human seminal vesicles

The
seminal vesicle secretion appears in the later fractions of ejaculation.
Coagulation occurs immediately after ejaculation. This step is important
to allow all spermatozoa to be in contact with the ingredients in the
semen. Thus, seminal vesicle secretion may promote sperm motility, increase
stability of sperm chromatin, and suppress the immune activity in the
female reproductive tract to avoid rejection of spermatozoa and embryo
(in case of fertilization) that have antigens foreign to women.

5.1
Coagulation

At
ejaculation, semen is a liquid and after contacting with the seminal vesicular
secretion, it coagulates[33]. The major component of this coagulum
is semenogelin I, a 52-kDa protein expressed exclusively in the seminal
vesicles[34,35]. The protein is rapidly cleaved after ejaculation
by the chymotrypsin-like prostatic protease, prostate-specific antigen
(PSA) to generate peptides of various biological activities that were
found on and inside spermatozoa. Coagulation fails to occur in ejaculates
with decreased seminal vesicle activity[36]. Poor coagulation
was also related to poor sperm motility[37].

5.2
Semen consistency

The
consistency of semen seems to be also related to seminal vesicle function[27].
The normal semen consistency is viscous. If the viscosity is abnormally
increased, it may be associated with infertility. High seminal viscosity
has been associated with hypofunction of the seminal vesicles[27,38].
Semen with high viscosity has low sperm motility. Male pseudo-hermaphrodites
with 5 alpha-reductase-2 deficiency have diminished values of dihydrotestosterone.
In these cases, low semen volume and high seminal viscosity were also
observed[39].

Semen
with high seminal viscosity was also associated with high sperm chromatin
stability in situations when a zinc-chelating agent is present[38].
Hypofunction of the seminal vesicle may affect the sperm chromatin stability,
as high seminal viscosity was related to hypofunction of these glands.

5.3
Sperm motility
enhancers

Several
products of the seminal vesicles are stimulators of sperm motility. These
are potassium[40], bicarbonate[41,42], magnesium[43],
19-OH-prostaglandin[44], and prolactin[45,46]. Bicarbonate
stimulates sperm motility through an action on the adenylate cyclase system
by increasing the production of cAMP[41,42]. Human semen contains
large amounts of prostaglandins produced mainly in the seminal vesicles[47].
Vasectomy does not affect semen prostaglandin concentration[48].
Sperm motility seems to be related to PGE, PGF, 19-OH-PGE and 19-OH-PGF[49,50].
Prolactin is found in seminal plasma of fertile and infertile men[46].
Prolactin in semen is secreted preferentially by the seminal vesicles[47,51]
and is related to sperm motility[45,46].

5.4
Sperm motility
inhibitor

Human
seminal plasma contains a sperm motility inhibitor (SPMI) that originates
from the seminal vesicle in a precursor form. This precursor is degraded
into smaller peptides by prostatic proteases shortly after ejaculation.
The SPMI precursor was found to be almost identical to semenogelin[52].
The SPMI precursor was found to inhibit sperm motility in a concentration-dependent
manner. The motility of SPMI-immobilized spermatozoa was partially recovered
after washing off[52].

5.5
Antioxidant function
of the seminal vesicles

As
many as 25% of semen samples from infertile men produce high levels of
reactive oxygen species (ROS)[53]. The higher levels of ROS
produced by damaged spermatozoa have been believed to be associated with
loss of motility and decreased sperm-oocyte fusion capacity[54].
Leucocytes produce more ROS than spermatozoa[55]. Although
ROS has been known to be an essential prerequisite for the normal functioning
of many cells, excessive exposure may be harmful to spermatozoa[56].
In addition, oxidative stress occurs even in patients with very low leucocyte
counts and may therefore impair fertility[57].

Ascorbic
acid is secreted by the seminal vesicles[60,61] and plays a
significant role, in association with antioxidant defenses that preserve
the functional competence of spermatozoa exposed to an oxidative attack[56].
Ascorbic acid may be oxidized by cooper, thus diminishing the protective
activity. This is important, since there are situations where cooper is
increased as in some pathological situations or in smokers.

Another
product of the seminal vesicle, semenogelin and its degradation products,
may be natural regulators of sperm capacitation. They prevent capacitation
process from occurring prematurely. The action may involve an interference
with the superoxide anion generation[62].

5.6
Immunology

Seminal
vesicles secrete antigens that seem to prevent female immune response
against spermatozoa[63] and embryo[64]. The seminal
vesicles secrete antigens of IgG-Fc receptor III that could protect spermatozoa
from IgG-mediated destruction and from antibody-mediated cellular cytotoxicity[63].
The seminal vesicles are also the source of seminal plasma trophoblast
lymphocyte cross-reactive (TLX) antigen[64]. TLX antigen is
absent from seminal plasma in congenital agenesis of seminal vesicles[65].This is supportive for the origin of the seminal plasma TLX antigens
from the seminal vesicles.

The
maternal recognition of allotypic TLX antigens is proposed to be involved
in the immunologic acceptance of the allogenic fetus. The presence of
TLX antigens in seminal plasma suggests that sensitization can occur before
fertilization and implantation[64]. The release of TLX antigens
by seminal vesicles could represent a mechanism of priming mother's immune
function for normal implantation and pregnancy[65,66]. Maternal
Fc-gamma receptor blocking antibodies have been linked to pregnancy success.
Idiotype-antiidiotype regulated maternal responses to TLX are proposed
to be necessary for successful pregnancy. Conformational site induced
by C3b (iC3) binding to MCP (membrane cofactor protein) may be responsible
for TLX allotypy[67].

Three
sperm-coat antigens have also been identified to be originated from the
human seminal vesicles: MHS-5 antigen[68], lactoferrin (80
KDa)[69], and ferriplan (15 KDa)[70,71]. Although
the iron-chelating protein lactoferrin is secreted by the seminal vesicles,
the precise role of lactoferrin in semen is unclear. Lactoferrin was increased
in oligozoospermia[72].

Under
the presence of leukocytospermia, adequate seminal vesicle function seems
to be necessary for immunosuppression, normal seminal quality, and therefore,
normal fertility. Sperm count, sperm motility, and sperm morphology were
affected in men with both leukocytospermia and hypofunction of the seminal
vesicles, whereas men with both leukocytospermia and normal seminal vesicle
function had normal seminal quality[26] . These findings are
in agreement with the suggestion that function of the seminal vesicle is
important to prevent the deleterious effect of white blood cells on the
seminal quality. Granulocytes were more related to seminal vesicle dysfunction
and sperm motility changes[73].

5.7
Sperm chromatin
stability

DNA
packing during the transformation of round spermatids into spermatozoa
involves the replacement of somatic-type histones with basic proteins,
which are rich in arginin and cystein, and are termed protamines. During
epididymal transit the formation of S-S cross bridges between the protamin-cystein
residue occurs, assuring a stable condensation of the nucleoprotein complex.
Nuclear condensation of sperm is stabilized further by zinc, which interchelates
between the free amino groups of arginin and the free thiol groups of
cystein[74]. This further stabilization occurs after ejaculation.

Zinc
bound to metallothionein, which is secreted mainly from the prostate gland,
is one factor that contributes to the chromatin stabilizing effect of
human prostatic fluid[75]. This effect occurs after ejaculation.
The amount of zinc present in the prostatic fluid that is taken by spermatozoa
needs to be regulated. Regulation occurs through the seminal vesicle secretion.
In fact, the stability of sperm chromatin was decreased in seminal plasma
dominated by vesicular fluid[76]. In addition, chromatin zinc
was related inversely to markers of seminal vesicular secretion[77].
In conclusion, prostatic fluid ensures appropriate zinc and stability
of sperm chromatin, whereas vesicular fluid regulates chromatin stability
by reducing chromatin zinc content. Content of zinc in sperm chromatin
is regulated by the action of zinc ligands of seminal vesicular origin[77].

Normally,
chromatin decondensation and nuclear swelling take place when the spermatozoa
penetrate the egg cytoplasm, and infertility may result if nuclear swelling
occurred before fertilization, because chromatin compactness is required
for the successful penetration of the oocyte vestments. In vitro,
in the presence of SDS and ethylendiamine tetra-acetic acid (EDTA), a chelating
agent that binds zinc, the sperm chromatin becomes decondensed. We have
demonstrated that hypofunction of the seminal vesicles was associated with
high sperm stability in the presence of SDS and EDTA[29]. The
effect of the function of seminal vesicles on sperm chromatin stability
seems to be due to the fact that seminal vesicles secrete high-molecular-weight
zinc ligands that reduce zinc content in sperm chromatin[79].
In cases of hypofunction of the seminal vesicles, if the content of zinc
available for the sperm chromatin increases, then sperm stability will increase.
Chromatin decondensation and nuclear swelling when spermatozoa penetrate
the egg cytoplasm are important for fertilization. Therefore, high sperm
stability may produce infertility.

5.8
Other substances
secreted by the seminal vesicles

Insulin
or an insulin-like peptide found in human seminal plasma was secreted
mainly by the seminal vesicles[80,81]. The insulin levels were
higher in the seminal plasma than in the serum[82]. The functional
significance of insulin in the seminal plasma is unknown.

Glycodelins
are 28 to 30 kDa glycoproteins synthesized in various glands, notably in
the male and female reproductive organs. Glycodelin A is purified from human
mid-trimester amniotic fluid, where it is secreted from the decidualized
endometrium. Glycodelin S is synthesized in the male reproductive tract,
mainly in the seminal vesicles[83]. Human endometrium-derived
glycodelin A temporally expressed in the latter half of the menstrual cycle,
consists of unique sialylated and fucosylated lacdi Nac oligosaccharide
sequences, and inhibits sperm-egg binding. By contrast, glycodelin-S from
seminal vesicles has no such oligosaccharide sequences and no contraceptive
activity[84].

Surgical
treatment has been used for ejaculatory duct obstruction. Ejaculatory
duct obstruction was considered in patients with low to normal ejaculate
volume, azoospermia or oligospermia, decreased motility, normal serum
gonadotropin and testosterone levels, absent or low fructose in the ejaculate
and evidence of obstruction on transrectal ultrasonography. Transurethral
resection of ejaculatory ducts resulted in improvement of ejaculate volume,
sperm count and sperm motility as early as 3 months after treatment. The
pregnancy rate is still low, which could be related to the hazardous effects
of urinary reflux into the ejaculatory ducts or functional abnormalities
of the seminal vesicle[86].

Depending
on the localization of the obstruction site, either a microsurgical reconstruction
(tubulovasostomy, vasovasostomy) or a transurethral resection of the ejaculatory
ducts can be done[87].Ejaculatory duct obstruction due to cysts appears to respond best
to surgical treatment. Such treatment may also decrease the need for IVF/ICSI
in many cases and allow IVF/ICSI to be performed with ejaculated rather
than surgically retrieved sperm[24].

In
conclusion, the normal function of the seminal vesicle is important for
fertility. Parameters as motility, sperm chromatin stability, and immune
protection may be affected in cases of hypofunction of the seminal vesicles.